The goals of this project are to characterize severe chronic infections with Epstein-Barr virus, to ascertain whether Epstein- Barr virus, the new human B lymphotrophic herpes virus, or other infectious agents can initiate a syndrome of chronic fatigue, and to characterize multiple aspects of the chronic fatigue syndrome. To date this research project has involved nearly 150 patients. Included are six patients with severe chronic Epstein-Barr virus infections. During the past year we began to use in-situ hybridization to study EBV gene expression in the tissues of these severely ill patients. All of the patients were proven to have increased levels of EBV RNA. On this oasis and on the basis of other historical, clinical and serologic features of these patients, we have proposed criteria by which severe chronic EBV infection can be diagnosed. We initiated a detailed survey of our patient population for evidence of prior HBLV infection. Initial controlled seroprevalence studies showed seropositivity to be higher in patients with chronic fatigue. Detailed neurologic, neuroendocrinologic, and neuropsychologic studies were conducted in selected patients with chronic fatigue. To date we have found no reproducible abnormalities in the chronic fatigue patients but for a high prevalence of depression and other neurosis. Having shown acyclovir to not benefit patients with the chronic fatigue syndrome, we conducted a series of open therapeutic trials involving doxepin, H1 blockers, and doxycycline. None of these have yielded impressive benefits. Trials involving other classes of anti-depressant drugs are now being considered. In collaboration with investigators elsewhere we have formulated research criteria for the chronic fatigue.